Acute graft versus host disease (GHVD) remains a major source of morbidity and transplant-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HCT). Despite advances in GVHD prophylactic regimen, significant (grade II-IV) acute GVHD that requires systemic treatment with high dose steroids occurs in 50-70% of HCT recipients of transplants from HLA-matched unrelated donor or partially HLA-matched donors. Outcomes for patients developing acute GVHD remain poor and new prophylactic strategies are needed. The University of Michigan BMT program has made seminal contributions to the understanding of GVHD pathophysiology and to the translation of promising new approaches into clinical trials. The University of Michigan was chosen to be a charter member of the BMT CTN at its inception ten years ago, and it has made key contributions to the success of the network, including a chairmanship of the steering committee, chairmanships of two protocols, additional memberships in six protocols, and the organization and hosting of the highly successful State of the Science Symposium in 2007. This application proposes, in specific Aim I, the comparison of two novel GVHD prophylaxis-required (etanercept vs pentostatin/ATG) in a multicenter, randomized Phase II protocol, the preliminary data for which having been generated at the University of Michigan and MD Anderson. Specific Aim 2 proposes to validate a four biomarker panel (IL2Rd, TNFRI, Elafin and Reg3a) for its ability to predict the onset of GVHD from plasma samples taken early after transplant from patients participating in the proposed trial. If validated, this biomarker panel could be used in subsequent BMT CTN trials to guide the preemptive treatment of acute GVHD. RELEVANCE (See instructions): This grant will make the University of Michigan a Core Center for the BMT CTN in order to conduct multi- center clinical trials in BMT patients.